Circulating thymic hormone activity and thymic histology were studied in patients undergoing open heart surgery. Plasma thymic hormone activity was measured using a bioassay based upon thymocyte antigen induction on null mouse lymphocytes. Activity was highest at 15-30 yr of age and declined thereafter, being negligible after the sixth age decade. The age-related decline of circulating thymic hormone activity correlated, in general, with progressive thymic involution. However, hormone activity was detected in plasma from some cases with advanced involution, suggesting that the normal young thymus may have considerable functional reserve.

Thymopoietin is a thymic hormone that induces differentiation of thymocytes from precursor cells which arise in hemo oietic tissues. This paper describes a sensitive in vitro assay Ior the induction of Thy 1.2 antigen on null lymphocytes from germ-free athymic (nu/nu) mice. The sensitivity and specificity of the bioassay were increased by adding hig concentrations of ubiquitin (a nonspecific inducer) to the induction incubations. The bioassay was sufficiently sensitive to detect thymopoietin at <0.25 ng/ml. A dose-response relationship was shown between thymopoietin concentration and the percentage of cells induced to eress Thy 1.2 antigen. When normal human plasma was assayed, induction was registered with activity corresponding to thymopoietin at >1 ng/ml in plasma from infants or young adults. Activities in the thymopoietin range of 0.25 ng/ml were registered with plasma from healthy subjects over 50 years of age. Thymectomy was followed by loss of this inductive activity from the plasma. This bioassay permits clinical studies on T (thymus-derived) cell inducers released by the human thymus into the circulation. The function of the thymus is to promote differentiation of lymphocytes (T cells) that participate in effecting and regulating immune responses. Abnormalities of the thymus have been detected with certain human diseases such as myasthenia gravis (1), systemic lupus erythematosus (2), and immune deficiency states (3-5). Thymic dysfunction may be implicated in a broader range of human disorders and also with aging (1). The lack of sensitive and precise tests for thymic function has hampered attempts to clarify the clinical significance of this immunologic organ.Thymopoietin (molecular weight 5562) is a polypeptide hormone of defined amino acid sequence (6) that induces differentiation of precursor lymphoid cells to thymocytes (7) and also has secondary effects upon neuromuscular transmission (8). Thymopoietin is secreted by epithelial cells of the thymus (9). Lymphocytes that differentiate under the influence of thymopoietin subsequently give rise to distinct subclasses of T cells with potential to develop discrete effector, helper, or suppressor functions after encounter with antigen (10). The relationship of thymopoietin to the later stages of the functional differentiation of T cells remains to be elucidated.Thymopoietin can be measured in vitro by its ability to differentiate precursor cells from bone marrow or spleen to cells that express characteristic surface antigens of T cells (7,11,12). Induction of T cell differentiation by thymopoietin is accomplished by the generation of cyclic AMP (13), which accounts for the ability of other agents that elevate intracellular cyclic AMP to induce T cell differentiation in a relatively nonspecific fashion (14 (17); this may be due to null lymphocyte membranes having distinct receptor sites for thymopoietin and ubiquitin.We have utilized these differences in induction with thymopoietin and ubiquitin to develop a sensitive bioassay for thymopoietin. ...